JP2023537293A - Method for preparing forodesine - Google Patents

Abstract

TECHNICAL FIELD The present invention relates to the technical field of chemical synthesis, and specifically includes the step of treating a compound of formula VII with an acid to produce a compound of formula I. Concerning the method of preparation. This method has few synthesis steps, stable raw materials, easy preparation, easy control of the reaction process, high overall yield and purity, and is suitable for industrial preparation.

Description

This application claims priority benefit based on Chinese Application No. 202010752502.5 filed on July 30, 2020, the disclosure of which is incorporated herein by reference in its entirety.

TECHNICAL FIELD The present invention is in the technical field of chemical synthesis and relates to a process for the preparation of forodesine.

BACKGROUND OF THE INVENTION Phorodesine, also known as BCX-1777, is a purine nucleoside phosphorylase (PNP) inhibitor. Forodesine was approved in the United States in 2004 as an orphan drug for the treatment of T-cell non-Hodgkin's lymphoma and chronic myelogenous leukemia. It was approved in the European Union as an orphan drug for the treatment of acute lymphocytic leukemia, cutaneous T-cell lymphoma and chronic lymphocytic leukemia in 2006, 2007 and 2010, respectively. In 2017, forodesine was approved in Japan for the treatment of relapsed/refractory peripheral T-cell lymphoma.

First-line treatment options for peripheral T-cell lymphoma are primarily combination chemotherapy (including cyclophosphamide, doxorubicin, vincristine, and prednisone) and brentuximab vedotin (ADCETRIS®). Treatment options for relapsed/refractory peripheral T-cell lymphoma are limited and ineffective. Currently, three histone deacetylation inhibitors, namely thidamide, romidepsin, and belinostat, are in common use, where thidamide is only approved in China and romidepsin and belinostat are only approved in the United States. ing. As a new nucleoside metabolism inhibitor, forodesine can effectively inhibit T-cell function and is a valuable agent for the treatment of relapsed/refractory peripheral T-cell lymphoma.

In addition, forodesine is also a key intermediate required for the synthesis of the broad-spectrum antiviral drug gallidesivir (BCX-4430) and is essential for the synthesis of BCX-4430.

However, the industrial production of forodesine is very difficult. According to literature reports (Nature, 2014, 508, 402-405), the currently used industrial production scheme is as follows.

In this scheme, secondary amine (8) is used as starting material and is chlorinated and dechlorinated to give imine (10). The bromopurine derivative (2) is lithiated by the action of n-butyllithium, then subjected to an addition reaction with imine (10), and the obtained secondary amine intermediate is protected with Boc to give intermediate (11). which is then hydrogenated to remove the BOM protecting group and heated with concentrated hydrochloric acid to remove other protecting groups to give forodesine hydrochloride, which is subjected to ion exchange resin and recrystallization to final purify to obtain forodesine.

In this preparation scheme, the preparation of the raw secondary amine (8) is complicated and expensive, and the cost of raw materials is high. The imines produced by the two-step transformation have low yields, are unstable, and are not easily stored. Removal of the BOM protecting group of the heterocycle requires hydrogenation, which requires special equipment, carries certain risks, and all these factors do not lend themselves to industrial scale production.

To improve the above scheme, patent application US20180258091A1 discloses a new process as follows. In this scheme, n-hexyllithium was used in place of n-butyllithium and the brompurine derivative (2) was lithiated at -15°C, which reduces the low temperature requirements of the reactor and also was modified to remove the BOM protecting group with concentrated hydrochloric acid to avoid hazardous high pressure hydrogenation conditions.

Although the above scheme provides an improved method for the addition and removal of BOM protecting groups, n-hexyllithium is expensive and difficult to obtain, and the method still uses secondary amines (8) as raw materials. However, problems such as cumbersome preparation steps, high cost, imine instability, and storage difficulties remain unsolved.

Therefore, it is of great significance and high application value to develop a synthetic scheme for forodesine, which has easy availability of raw materials, simple operation, low cost, and potential for industrialization.

Contents of the Invention It is an object of the present invention to provide a new method for preparing forodesine, and another object of the present invention is to provide a method for preparing forodesine using readily available raw materials. Another object of the present invention is to provide a method for preparing forodesine with a smaller reaction scheme, and another object of the present invention is to provide a method that is easy to operate, easy to control the operation, and safe. Another object of the present invention is to provide a low-cost method for preparing forodesine, and another object of the present invention is to provide a method for preparing forodecine that is suitable for scale-up production. To provide a method for the preparation of Pholodesine.

を含み、式中、
Ｒ_１は、アミノ保護基、例えばカルボベンゾキシ（Ｃｂｚ）、ｔｅｒｔ－ブトキシカルボニル（Ｂｏｃ）、メトキシカルボニル、エトキシカルボニル、フタロイル（Ｐｈｔ）、２，４－ジメトキシベンジル（ＤＭＢ）、ベンジル（Ｂｎ）、ベンジルオキシメチル（ＢＯＭ）であり；
Ｒ_２は、メチル又はエチルであり；
Ｒ_３、Ｒ_４、Ｒ_５は、それぞれ独立してヒドロキシル保護基、例えばトリメチルシリル（ＴＭＳ）、ｔｅｒｔ－ブチルジメチルシリル（ＴＢＤＭＳ）、ベンジル（Ｂｎ）、ｐ－メトキシベンジル（ＰＭＢ）、２－テトラヒドロピラニル（ＴＨＰ）、メトキシメチル（ＭＯＭ）、１－エトキシエチル（ＥＥ）であり；
Ｒ_６は、アミノ保護基、例えばカルボベンゾキシ（Ｃｂｚ）、ｔｅｒｔ－ブトキシカルボニル（Ｂｏｃ）、メトキシカルボニル、エトキシカルボニル、フタロイル（Ｐｈｔ）、２，４－ジメトキシベンジル（ＤＭＢ）、ベンジル（Ｂｎ）、ベンジルオキシメチル（ＢＯＭ）である。 To achieve the above objects, the present invention provides a process for preparing compounds of formula I, which process comprises
treating a compound of formula VII with an acid (e.g., concentrated hydrochloric acid) to make a compound of formula I;

including, where
R ₁ is an amino protecting group such as carbobenzoxy (Cbz), tert-butoxycarbonyl (Boc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), 2,4-dimethoxybenzyl (DMB), benzyl (Bn), benzyloxymethyl (BOM);
R ₂ is methyl or ethyl;
R ₃ , R ₄ , R ₅ are each independently a hydroxyl protecting group such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), benzyl (Bn), p-methoxybenzyl (PMB), 2-tetrahydropyrani (THP), methoxymethyl (MOM), 1-ethoxyethyl (EE);
R ₆ is an amino protecting group such as carbobenzoxy (Cbz), tert-butoxycarbonyl (Boc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), 2,4-dimethoxybenzyl (DMB), benzyl (Bn), benzyloxymethyl (BOM);

In some embodiments, in the method of preparing a compound of Formula I of the present invention, a compound of Formula VII is treated with concentrated hydrochloric acid.

In some embodiments, in the method of preparing a compound of Formula I of the present invention, a compound of Formula VII is treated with an acid under heating and reflux conditions.

In some embodiments, in the method of preparing a compound of Formula I of the present invention, a compound of Formula VII is treated with an acid under reflux conditions for 20-100 hours, such as 24-96 hours. , 36-84 hours, 48-72 hours.

In some embodiments, in the method of preparing a compound of Formula I of the present invention, a compound of Formula VII is treated with an acid by a method comprising the following operations:
a) dissolving the compound of formula VII in a first solvent to obtain a solution containing the compound of formula VII;
b) adding an acid (eg, concentrated hydrochloric acid) to a solution containing a compound of Formula VII and heating and refluxing.

In some embodiments, the first solvent of the invention is tetrahydrofuran or methanol.

In some embodiments, the first solvent of this invention is tetrahydrofuran.

In some embodiments, the method of preparing a compound of Formula I of the present invention comprises
i) removing the first solvent, adding ethanol to the resulting product and separating and collecting the solid;
ii) optionally purifying the solid obtained;
further includes

In some embodiments, in the method of preparing a compound of Formula I of the present invention, the method of purifying the resulting solid comprises:
iii) dissolving the resulting solid in water to obtain an aqueous solution;
iv) contacting the aqueous solution with a cation exchange resin, eluting with dilute hydrochloric acid (eg, 2-4 M hydrochloric acid), and collecting the eluate;
v) removing the solvent in the eluate and dissolving the product in dilute hydrochloric acid (eg 0.5-1.5 M hydrochloric acid), heating to 40-60° C. (eg 45-55° C.) and cooling to room temperature; and,
vi) adding ethanol to the product obtained in v) and stirring at room temperature for 6-10 hours to precipitate a solid;
vii) cooling to 0° C. and standing;
viii) recovering the solids;
further includes

In some embodiments, in compounds of Formula VII of the present invention, R ₁ is 2,4-dimethoxybenzyl (DMB), benzyl (Bn), or benzyloxymethyl (BOM).

In some embodiments, in compounds of Formula VII of the present invention, R ₁ is 2,4-dimethoxybenzyl (DMB).

In some embodiments, in compounds of formula VII of the present invention, R ₁ is benzyl (Bn).

In some embodiments, in compounds of Formula VII of the present invention, _R1 is carbobenzoxy (Cbz).

In some embodiments, in compounds of Formula VII of the present invention, R ₁ is tert-butoxycarbonyl (Boc).

In some embodiments, in compounds of Formula VII of the present invention, R ₁ is methoxycarbonyl.

In some embodiments, in compounds of Formula VII of the present invention, R ₁ is ethoxycarbonyl.

In some embodiments, in compounds of Formula VII of the present invention, R ₁ is phthaloyl (Pht).

In some embodiments, in compounds of Formula VII of the present invention, _R2 is methyl.

In some embodiments, in compounds of Formula VII of the present invention, R ₃ , R ₄ and R ₅ are each independently benzyl (Bn), p-methoxybenzyl (PMB), methoxymethyl ( MOM), or 1-ethoxyethyl (EE).

In some embodiments, in compounds of Formula VII of the present invention, R ₃ , R ₄ and R ₅ are each independently p-methoxybenzyl (PMB).

In some embodiments, in compounds of Formula VII of the present invention, _R3 , _R4 , and _R5 are each independently methoxymethyl (MOM).

In some embodiments, in compounds of Formula VII of the present invention, R ₃ , R ₄ and R ₅ are each independently 1-ethoxyethyl (EE).

In some embodiments, in compounds of Formula VII of the present invention, _R3 , _R4 , and _R5 are each independently trimethylsilyl (TMS).

In some embodiments, in compounds of Formula VII of the present invention, R ₃ , R ₄ , and R ₅ are each independently tert-butyldimethylsilyl (TBDMS).

In some embodiments, in compounds of Formula VII of the present invention, R ₃ , R ₄ and R ₅ are each independently 2-tetrahydropyranyl (THP).

In some embodiments, in compounds of Formula VII of the present invention, R ₆ is carbobenzoxy (Cbz), tert-butoxycarbonyl (Boc), methoxycarbonyl, or ethoxycarbonyl. In some embodiments, in compounds of Formula II of the present invention, _R6 is carbobenzoxy (Cbz).

In some embodiments, in compounds of Formula VII of the present invention, _R6 is methoxycarbonyl.

In some embodiments, in compounds of Formula VII of the present invention, _R6 is ethoxycarbonyl.

In some embodiments, in compounds of Formula VII of the present invention, _R6 is phthaloyl (Pht).

In some embodiments, in compounds of Formula VII of the present invention, R ₆ is 2,4-dimethoxybenzyl (DMB).

In some embodiments, in compounds of Formula VII of the present invention, _R6 is benzyl (Bn).

In some embodiments, in compounds of Formula VII of the present invention, _R6 is benzyloxymethyl (BOM).

In some embodiments, in compounds of Formula VII of the present invention, R ₁ is benzyloxymethyl (BOM).

In some embodiments, in compounds of Formula VII of the present invention, _R2 is ethyl.

In some embodiments, in compounds of Formula VII of the present invention, _R3 , _R4 , and _R5 are each independently benzyl (Bn).

In some embodiments, in compounds of Formula VII of the present invention, R ₆ is tert-butoxycarbonyl (Boc).

In some embodiments, in the compounds of Formula VII of the present invention, R ₁ is benzyloxymethyl (BOM), R ₂ is methyl, R ₃ , R ₄ , R ₅ are each independently is benzyl (Bn) and R ₆ is tert-butoxycarbonyl (Boc).

で表される化合物の１位にアミノ保護基Ｒ_６を導入することを含み、式中、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、Ｒ_５、及びＲ_６の定義は、式ＶＩＩの定義と同じである。 In some embodiments, the method of preparing a compound of Formula I of the present invention further comprises preparing a compound of Formula VII, which comprises Formula VI

wherein the definitions of R ₁ , R ₂ , R _{3 ,} R ₄ , R ₅ and R ₆ are the same as those of Formula VII is the same as

Since the compound of formula VI is prone to oxidation, introduction of an amino protecting group into the compound of formula VI provides the compound of formula VII with stable properties, and subsequent separation and Convenient for purification.

In some embodiments, in compounds represented by Formula VII, R ₆ is tert-butoxycarbonyl (Boc) and the definitions of R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are as defined herein , which is obtained by Boc protection of compounds of formula VI. Preferably, a compound of formula VI is reacted with Boc anhydride under basic conditions to give a compound of formula VII. More preferably, a compound of formula VI is reacted with Boc anhydride in the presence of sodium hydroxide to give a compound of formula VII.

で表される化合物を還元することを含み、式中、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、及びＲ_５の定義は、式ＶＩＩの定義と同じである。 In some embodiments, the method of preparing a compound of Formula I of the present invention further comprises preparing a compound of Formula VI, which comprises Formula V

wherein the definitions of R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are the same as for Formula VII.

In some embodiments, in the methods of preparing compounds of Formula I of the present invention, the compound of Formula V is reduced with a reducing agent.

In some embodiments, in the methods of preparing compounds of Formula I of the present invention, the compound of Formula V is reduced with a reducing agent in a second solvent.

In some embodiments, the reducing agent of the present invention is zinc powder, iron powder, or indium powder.

In some embodiments, the reducing agent of the present invention is zinc powder.

In some embodiments, the reducing agent of the present invention is iron powder.

In some embodiments, the reducing agent of the present invention is indium powder.

In some embodiments, the second solvent of the present invention is a mixed solvent of acetic acid and methanol, trifluoroacetic acid (TFA), 4-8 M (eg, 6 M) hydrochloric acid, or a saturated aqueous solution of NH ₄ Cl. be.

In some embodiments, the second solvent of the present invention is a mixed solvent of acetic acid and methanol, preferably a mixed solvent of acetic acid and methanol in a volume ratio of 1:3 to 8, such as a volume ratio of 1:4. ˜6 of a mixed solvent of acetic acid and methanol, such as a mixed solvent of acetic acid and methanol with a volume ratio of 1:5.

In some embodiments, the second solvent of the present invention is trifluoroacetic acid (TFA), 4-8 M (eg, 6 M) hydrochloric acid, or a saturated aqueous solution of NH ₄ Cl.

In some embodiments, the second solvent of the present invention is trifluoroacetic acid (TFA).

In some embodiments, the second solvent of the present invention is 4-8M (eg, 6M) hydrochloric acid.

In some embodiments, the second solvent of the present invention is a saturated aqueous solution of _NH4Cl .

In some embodiments, in the method of preparing a compound of Formula I of the present invention, the molar ratio of the reducing agent to the compound of Formula V is 15-25:1, such as 18-22: 1, 20:1.

ａ）式ＩＩで表される化合物を金属リチウム試薬で処理して、式ＩＩＩで表される化合物を生成する工程と、
ｂ）式ＩＩＩで表される化合物を式ＩＶで表される化合物と反応させて、式Ｖで表される化合物を作成する工程と、
を含み、
式中、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、及びＲ_５の定義は式ＶＩＩの定義と同じであり、Ｘはハロゲン、好ましくは臭素原子、及びヨウ素原子であり、例えば臭素原子である。 In some embodiments, the method of preparing a compound of Formula I of the present invention further comprises a method of preparing a compound of Formula V, which comprises

a) treating a compound of Formula II with a metallic lithium reagent to produce a compound of Formula III;
b) reacting a compound of formula III with a compound of formula IV to form a compound of formula V;
including
wherein the definitions of R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are the same as for formula VII, X is halogen, preferably bromine and iodine, for example bromine .

A compound of formula III reacts with a compound of formula IV to produce a pair of isomers with a diastereoselectivity of 7:1, the major product being of formula V. is a compound. Compounds of Formula V are reduced to compounds of Formula VI, and this intermediate is readily oxidized. An amino protecting group is introduced into the compound of formula VI to give the compound of formula VII with stable properties so that the diastereoisomers produced in the above reaction steps can be easily separated. can.

In some embodiments, the metallic lithium reagents of the present invention are n-butyllithium, tert-butyllithium, phenyllithium, and sec-butyllithium.

In some embodiments, the lithium metal reagent of the present invention is n-butyllithium.

In some embodiments, the lithium metal reagent of the present invention is tert-butyllithium.

In some embodiments, the lithium metal reagent of the present invention is phenyllithium.

In some embodiments, the lithium metal reagent of the present invention is sec-butyllithium.

In some embodiments, in the methods of preparing compounds of Formula I of the present invention, the compound of Formula II is treated with a lithium metal reagent in a third solvent.

In some embodiments, the third solvent of the invention is methyl tert-butyl ether, tetrahydrofuran (THF), anisole, n-hexane, or toluene.

In some embodiments, the third solvent of the invention is methyl tert-butyl ether.

In some embodiments, the third solvent of the present invention is anhydrous methyl tert-butyl ether.

In some embodiments, the third solvent of the present invention is tetrahydrofuran (THF).

In some embodiments, the third solvent of the invention is anisole.

In some embodiments, the third solvent of this invention is n-hexane.

In some embodiments, the third solvent of the invention is toluene.

In some embodiments, in the method of preparing a compound of Formula I according to the present invention, the compound of Formula II is treated with a lithium metal reagent under conditions of -60°C to 0°C (eg -40°C). , −20° C.).

In some embodiments, in the method of preparing a compound of Formula I according to the present invention, a compound of Formula II is treated with a lithium metal reagent under conditions of -40°C to 0°C.

In some embodiments, in the method of preparing a compound of Formula I according to the present invention, a compound of Formula II is treated with a lithium metal reagent under conditions of -60°C to -20°C. .

In some embodiments, in the method of preparing a compound of Formula I according to the present invention, the compound of Formula II is treated with a lithium metal reagent under conditions of -40°C to -20°C. .

In some embodiments, in the method of preparing a compound of Formula I according to the present invention, the molar ratio of the lithium metal reagent to the compound of Formula II is 1 to 1.5:1, such as 1 .2:1.

In some embodiments, in the method of preparing a compound of Formula I according to the present invention, a compound of Formula III is reacted with a compound of Formula IV in a third solvent.

In some embodiments, in the method of preparing a compound of Formula I according to the present invention, the feed molar ratio of the compound of Formula II to the compound of Formula IV is 1.4 to 2 .2:1, such as 1.6 to 2:1, such as 1.8:1.

In some embodiments, in a method of preparing a compound of Formula I according to the present invention, a compound of Formula III is combined with a compound of Formula IV at a temperature of -60°C to 0°C (eg -40°C). °C, -20°C).

In some embodiments, in the method of preparing a compound of Formula I according to the present invention, a compound of Formula III is combined with a compound of Formula IV under conditions of -40°C to 0°C. react.

In some embodiments, in the method of preparing a compound of Formula I according to the present invention, a compound of Formula III is combined with a compound of Formula IV under conditions of -60°C to -20°C. react with.

In some embodiments, in the method of preparing a compound of Formula I according to the present invention, a compound of Formula III is combined with a compound of Formula IV under conditions of -40°C to -20°C. react with.

式中、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、Ｒ_５、及びＲ_６の定義は、式ＶＩＩの定義と同じである。 The present invention further provides an intermediate compound of Formula V, Formula VI, or Formula VII,

wherein the definitions of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are the same as for Formula VII.

In some embodiments, the intermediate compound is selected from the group consisting of:

The present invention
a) using the method of the invention to prepare a compound of Formula I;
b) converting a compound of formula I into the free form of forodecine, or converting a compound of formula I into the desired salt of forodecine,
Further provided is a method of preparing forodesine or a salt thereof, comprising:

In the present invention, the compound of formula IV is a nitrone compound, such as a nitrone compound of IV, wherein R ₃ , R ₄ and R ₅ are each independently benzyl (Bn). , which can be prepared with reference to methods in the literature (Tetrahedron, 2009, 65, 93-100). Compounds of formula II wherein R ₁ is benzyloxymethyl (BOM), R ₂ is methyl and X is a bromine atom are described in Journal of Organic Chemistry, 2001, 66(17), 5723 -5730) can be prepared.

Definitions Unless defined otherwise below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technology used herein refer to technology as commonly understood in the art and are intended to include variations or permutations of equivalent technology that are apparent to those skilled in the art. While the following terms are believed to be well understood by those of ordinary skill in the art, the following definitions are provided to better describe the present invention.

The terms "include," "include," "comprise," "include," or "refer to," and other variations herein, are inclusive or open-ended and do not exclude other recited elements or method steps.

As used herein, the term "halogen" group is defined to include F, Cl, Br, or I.

As used herein, the term "concentrated hydrochloric acid" generally refers to hydrochloric acid having a mass fraction of 36% to 38% and a substance concentration of 12 mol/L.

As used herein, the term "dilute hydrochloric acid" refers to hydrochloric acid with a mass fraction of less than 20%.

Unless otherwise apparent from the context, all numerical values provided herein are modified by the term "about," i.e., numerical values disclosed herein refer not only to the numerical values themselves, but also to the numerical values modified by "about." Also includes For certain values used herein, the term "about" is within the range of normal tolerances in the art, e.g., ±10%, ±9%, ±8%, ±7%, ±6%. , ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, ±0.1%, ±0.05%, or ±0.01% It should be.

Beneficial Effects of the Invention:

The method of preparing the compound of Formula I forodesine hydrochloride provided by the present invention has one or more of the following advantages:
1) The raw materials and solvents used in this method are inexpensive and readily available;
2) This method uses nitrone compounds as raw materials, which are stable, easy to store, easy to prepare on a large scale, simple and convenient to prepare, and the associated reagents and solvents are inexpensive. can be easily obtained with , and the operation is simple;
3) The synthetic process of this method is easy to operate, the synthetic scheme is short, and the overall yield is high, for example about 30%;
4) the production cost of this method is low;
5) Phorodesine hydrochloride prepared by this method is highly pure, and the purity can reach greater than 99.8%, such as 99.9%;
6) The method is suitable for industrial production.

1 shows the ¹ H-NMR nuclear magnetic spectrum of forodesine hydrochloride of the present invention. 13 shows the ¹³ C-NMR nuclear magnetic spectrum of forodesine hydrochloride of the present invention. 1 shows an HPLC spectrum diagram of forodesine hydrochloride of the present invention. FIG.

Column: Agilent ZORBAX SB-C18, 4.6×150 mm, 5 μm;
Solvent: 0.1% TFA/ _H2O = 100%; flow rate: 0.3 mL/min;
Peak information (wavelength: 254 nm):

Specific Models for Implementing the Present Invention In order to further illustrate the technical effects of the present invention, the present invention is described in detail below through examples. The examples provided are merely illustrative of the method of the invention and are not intended to limit the invention in any way.

Unless otherwise specified, the reagents, methods and equipment used in the present invention are those conventional in the art.

Example: Preparation of Phorodesine Hydrochloride The compound of Formula 1, namely Phorodesine Hydrochloride, of the Examples of the present invention was prepared by the following synthetic scheme:

1) Preparation of compound 5:
Bromopurine derivative (2) (22.5 g, 64.7 mmol) was dissolved in anhydrous methyl tert-butyl ether (600 mL), cooled to −20° C., and n-butyllithium (2.5 M, 31 mL, 78 mmol) was slowly added. added dropwise. After the addition was complete, the mixture was stirred at −20° C. for 1 hour, then warmed to room temperature and stirred for 10 minutes, then cooled to −20° C., then treated with the nitrone (4) in methyl tert-butyl ether (50 mL). ) (15.0 g, 35.9 mmol) was slowly added dropwise. The resulting mixture was allowed to react at −20° C. for 15 hours and saturated ammonium chloride solution was added to quench the reaction. The resulting mixture was warmed to room temperature, diluted with ethyl acetate, the organic and aqueous layers were separated, the aqueous layer was extracted three times with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was was removed under reduced pressure to give the crude product of hydroxylamine (5), which was used directly in the next step without isolation and purification.

2) Preparation of compound 6:
The crude hydroxylamine (5) obtained in the previous step was dissolved in a mixed solvent of acetic acid and methanol (V/V=1:5, 60 mL) and zinc powder (47.0 g, 0.72 mol) was added. , the mixture was heated to reflux for 2 hours. The reaction solution is then cooled to room temperature, filtered through diatomaceous earth to remove insolubles, and the filtrate is concentrated and dehydrated to give the crude secondary amine (6), which can be used directly without isolation and purification. Used in the next step.

3) Preparation of compound 7:
The crude secondary amine (6) obtained in the previous step was dissolved in tetrahydrofuran (150 mL), 3M sodium hydroxide aqueous solution (150 mL, 0.45 mol) was added, the pH value of the solution was adjusted to 10, and BOC anhydrous (15.7 g, 71.8 mmol) was added and the resulting reaction solution was allowed to react at room temperature for 15 hours. After monitoring the completion of the reaction by LC-MS, the reaction solution was filtered through diatomaceous earth to remove insoluble matter. Tetrahydrofuran in the filtrate was distilled off under reduced pressure, the residue was diluted with ethyl acetate, the organic layer and aqueous layer were separated, the aqueous layer was extracted with ethyl acetate three times, the organic layers were combined, and the organic layers were dried over anhydrous sodium sulfate. , the solvent was distilled off under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V) = 5:1) to give a pale yellow oil (7) (11.0 g, 40%) was obtained. LC-MS m/z for C ₄₆ H ₅₁ N ₄ O ₇ [M+H] ⁺ calcd 771.4, found 771.4.

4) Preparation of Forodesine Hydrochloride Compound 7 (11.0 g) was dissolved in tetrahydrofuran (50 mL), concentrated hydrochloric acid (12 M (36%-38%), 100 mL) was added, and the resulting mixture was heated to reflux for 72 hours. , concentrated to dryness, filtered, and the solvent of the filtrate was evaporated under reduced pressure to obtain a reddish brown solid, to which ethanol (50 mL) was added, the reaction mixture was triturated, filtered, and the solid was collected to give crude forodesine. Hydrochloride salt (1) was obtained in about 78% yield.

5) Purification and Improvement of Forodesine Hydrochloride Solid forodesine hydrochloride was dissolved in water, the resulting mixture was filtered through a cation exchange resin (eluted with 5 L of 3M dilute hydrochloric acid), and the hydrochloric acid eluate was collected and concentrated to dryness. Solidified, the residue was dissolved in 1M dilute hydrochloric acid, heated to 50° C., then cooled to room temperature and ethanol was added slowly until a solid precipitated. The resulting mixture was stirred at 20° C. for 8 hours, then cooled to 0° C. and allowed to stand for 2 hours. The solid was collected by filtration and dried to give forodesine hydrochloride (about 3.0 g) as a white solid, the structure and purity characterization results of which are shown in FIGS. Met.

The overall yield for this example was about 30%.

^<1> H NMR (400 MHz, _CD3SOCD3 ) _[delta ] 12.38 (s, 1H), 12.18 (s, 1H), 10.47 (s, 1H), 8.45 (s, 1H), 7.89 (s, 1H), 7.65 (d, J = 4.0Hz, 1H), 5.60 (d, J = 4.0Hz, 1H), 5.50 (d, J = 4.0Hz, 1H) , 5.46 (t, J=4.0 Hz, 1H), 4.63 (d, J=8.0 Hz, 1H), 4.44-4.39 (m, 1H), 4.19-4. 15 (m, 1H), 3.74-3.71 (m, 1H), 3.50-3.46 (m, 1H). ^13C NMR (100 MHz, _CD3SOCD3 ) _? , 56.5. LC- _MS m/z _{for C11H15N4O4} [M+H] ⁺ calc'd 267.1; found _267.1 .

It should be noted that the foregoing examples are only used to describe the technical solutions of the present invention and do not limit the present invention. Although the technical solution of the present invention has been described in detail with reference to preferred embodiments, those skilled in the art will appreciate that the technical solution of the present invention can be modified or equivalent without departing from the spirit and scope of the present invention. It should be understood that permutations are possible, and all these modifications should fall within the protection scope of the present invention.

Claims (13)

A method for preparing a compound of Formula I, comprising:
treating a compound of formula VII with an acid to make said compound of formula I;

including
During the ceremony,
R ₁ is an amino protecting group such as carbobenzoxy (Cbz), tert-butoxycarbonyl (Boc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), 2,4-dimethoxybenzyl (DMB), benzyl (Bn), benzyloxymethyl (BOM);
R ₂ is methyl or ethyl;
R ₃ , R ₄ , R ₅ are each independently a hydroxyl protecting group such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), benzyl (Bn), p-methoxybenzyl (PMB), 2-tetrahydropyrani (THP), methoxymethyl (MOM), 1-ethoxyethyl (EE);
R ₆ is an amino protecting group such as carbobenzoxy (Cbz), tert-butoxycarbonyl (Boc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), 2,4-dimethoxybenzyl (DMB), benzyl (Bn), is benzyloxymethyl (BOM);
Method. 2. The method of claim 1, wherein said acid is concentrated hydrochloric acid. 2. The method of claim 1, wherein said compound of Formula VII is treated with said acid under heating to reflux conditions. 4. A method according to claim 3, wherein said compound of formula VII is treated with said acid under reflux conditions for 20-100 hours, such as 24-96 hours, 36-84 hours, and 48-72 hours. the method of. Said compound of Formula VII is treated with said acid by the following manipulations:
a) dissolving said compound of formula VII in a first solvent (e.g. tetrahydrofuran, methanol, preferably tetrahydrofuran) to obtain a solution containing said compound of formula VII;
b) adding said acid to a solution containing said compound of Formula VII and heating and refluxing;
A method according to any one of claims 1 to 4, which is treated by a method comprising said method comprising:
i) removing said first solvent, adding ethanol to the resulting product and separating and collecting the solid;
ii) optionally purifying the solid obtained;
further comprising
Preferably, the method of purifying the obtained solid comprises
iii) dissolving the obtained solid in water to obtain an aqueous solution;
iv) contacting the aqueous solution with a cation exchange resin, eluting with dilute hydrochloric acid (eg, 2-4 M hydrochloric acid), and collecting the eluate;
v) removing the solvent in the eluate and dissolving the product in dilute hydrochloric acid (eg 0.5-1.5 M hydrochloric acid), heating to 40-60° C. (eg 45-55° C.) and cooling to room temperature; process;
vi) adding ethanol to the product obtained in v) and stirring at room temperature for 6-10 hours to precipitate a solid;
vii) cooling to 0° C. and standing;
viii) collecting the solids;
2. The method of claim 1, comprising: preferably R ₁ is 2,4-dimethoxybenzyl (DMB), benzyl (Bn), or benzyloxymethyl (BOM);
preferably R ₂ is methyl;
preferably R ₃ , R ₄ , R ₅ are each independently benzyl (Bn), p-methoxybenzyl (PMB), methoxymethyl (MOM), or 1-ethoxyethyl (EE);
Preferably R ₆ is carbobenzoxy (Cbz), tert-butoxycarbonyl (Boc), methoxycarbonyl or ethoxycarbonyl,
The method of claim 1. preferably R ₁ is benzyloxymethyl (BOM);
preferably R ₂ is methyl;
preferably R ₃ , R ₄ , R ₅ are each independently benzyl (Bn);
Preferably R ₆ is tert-butoxycarbonyl (Boc),
8. The method of claim 7. said method comprising:
Compounds of Formula VI

wherein the definition of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ is defined in claims 1-4 and _6- the same as defined in any one of paragraph 8,
The method of any one of claims 1-4 and 6-8, further comprising a method of preparing said compound of formula VII comprising: said method comprising:
Compounds of Formula V

wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ are the same as defined in any one of claims 1-4 and 6-8. process,
further comprising a method of preparing said compound of Formula VI comprising
Preferably said compound of formula V is reduced with a reducing agent such as zinc powder, iron powder or indium powder, preferably zinc powder;
Preferably said compound of formula V is reduced with a reducing agent in a second solvent;
Preferably, said second solvent is a mixed solvent of acetic acid and methanol, trifluoroacetic acid (TFA), 4-8M (eg 6M) hydrochloric acid, or a saturated aqueous solution of NH ₄ Cl;
Preferably, the second solvent is a mixed solvent of acetic acid and methanol, preferably a mixed solvent of acetic acid and methanol in a volume ratio of 1:3-8, for example a mixed solvent of acetic acid and methanol in a volume ratio of 1:4-6. a mixed solvent, such as a mixed solvent in which the volume ratio of acetic acid and methanol is 1:5;
Preferably, the molar ratio of said reducing agent to said compound of formula V is 15 to 25:1, such as 18 to 22:1, 20:1,
10. The method of claim 9. said method comprising:
a) treatment of a compound of formula II with a metallic lithium reagent (e.g. n-butyllithium, tert-butyllithium, phenyllithium, sec-butyllithium, preferably n-butyllithium) to give a compound of formula III creating a compound that is
b) reacting said compound of formula III with a compound of formula IV to produce a compound of formula V;

further comprising a method of preparing said compound of Formula V comprising
wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined in any one of claims 1-4 and 6-8 and X is a halogen, preferably a bromine atom and an iodine atom, such as a bromine atom,
Preferably, said compound of formula II is dissolved in a third solvent such as methyl tert-butyl ether, tetrahydrofuran (THF), anisole, n-hexane or toluene, preferably methyl tert-butyl ether, such as anhydrous methyl tert-butyl ether. ) is treated with a metallic lithium reagent in
Preferably, said compound of formula II is treated with said metallic lithium reagent under conditions of -60°C to 0°C (eg -40°C, -20°C);
Preferably, the molar ratio of said lithium metal reagent to said compound of formula II is from 1 to 1.5:1, such as 1.2:1;
Preferably, said compound of formula III is dissolved in said third solvent (eg methyl tert-butyl ether, tetrahydrofuran (THF), anisole, n-hexane or toluene, preferably methyl tert-butyl ether, eg anhydrous methyl tert- reacting with said compound of formula IV in butyl ether);
Preferably, the feed molar ratio of said compound of formula II to said compound of formula IV is 1.4 to 2.2:1, such as 1.6 to 2:1, such as 1.8: is 1;
Preferably, said compound of formula III reacts with said compound of formula IV under conditions of -60°C to 0°C (eg -40°C, -20°C),
11. The method of claim 10. A compound of Formula V, Formula VI, or Formula VII,

wherein _R1 , _R2 , _R3 , _R4 , _R5 , _R6 are as defined in any one of claims 1, 7 and 8;
Preferably, said compound is

A compound selected from the group consisting of A method for preparing forodesine or a salt thereof, comprising:
a) preparing said compound of formula I using a process according to any one of claims 1-11;
b) converting said compound of formula I to the free form of forodesine or converting said compound of formula I to the desired salt of forodesine;
method including.